γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

Abstract Objective The cleavage of amyloid precursor protein by γ‐secretase is an important aspect of the pathogenesis of Alzheimer's disease. γ‐Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the γ‐secretase catalytic site. Our aim was to investigate whether γ‐secretase can be important for microglial phagocytosis of Alzheimer's disease β‐amyloid. Methods We investigated the role of γ‐secretase in microglia activity toward β‐amyloid phagocytosis in cell culture using γ‐secretase inhibitors and small hairpin RNA and presenilin‐deficient mice. Results We found that γ‐secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble β‐amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble β‐amyloid. Dysfunction in the γ‐secretase catalytic site led to an impairment in clearing insoluble β‐amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild‐type mice. Interpretation We suggest for the first time, a dual role for γ‐secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic β‐amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic β‐amyloid deposits. Further studies of γ‐secretase‐mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention. ANN NEUROL 2010